Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
AIDS is characaterized by a progressive depletion of T lymphocytes, particularly the helper-inducer subset having a CD4 surface antigen (CD4.sup.+). CD4.sup.+ lymphocytes are responsible for the induction of numerous functions of the human immune system.
No treatment is currently available to prevent or reverse the immunodeficiency of AIDS and ARC. Moreover, it is generally believed that an effective vaccine or therapy must be developed in order to prevent the transmission of HIV.
A number of compounds that interfere with viral replication have been developed to treat AIDS, including inhibitors of HIV reverse transcriptase (RT), such as nucleoside analogs including 3'-azido-3'-deoxythymidine (AZT, zidovidine) and 2', 3'-dideoxy nucleosides such as 2', 3'-dideoxyinosine (DDI, ddI) and 2', 3'-dideoxycytidine (DDC, ddC).
To date only AZT has been approved by the U.S. FDA for early treatment of HIV positive individuals as well as individuals with ARC and AIDS. However, AZT is frequently toxic, causing bone marrow suppression resulting in anemia, leukopenia and thrombocytopenia. Also, AZT-resistant HIV strains have been observed after six months of AZT treatment. DDI and DDC have been FDA approved for treatment of individuals with ARC and AIDS only in combination with AZT.
Consequently, there is a continuing need for new effective and safe treatments for HIV infection and the associated HIV disease, including AIDS.
The aspartic acid protease encoded by HIV is critical for replication of the virus (Kohl, et al., Proc. Natl. Acad. Sci. 85:4686-4690 (1988)). HIV protease is responsible for specific cleavages of the viral gag/pol gene products, which are precursors of essential viral structural proteins and essential enzymes including reverse transcriptase, integrase, and the protease itself (Ratner et al., Nature 316:277-284 (1985); Schneider and Kent, Cell 54:363-368 (1988); Darke et al., Biochem. Biophys. Res. Commun. 156: 297-303 (1988)). Inhibition of HIV protease by synthetic inhibitors during infection of cells in cell culture leads to a reduction in the amount of infectious virus particles produced (McQuade et al., Science 247: 454-456 (1990)). This inhibition of HIV by HIV protease inhibitors is presumably due primarily to the insufficient processing of the p55 gag polyprotein to the essential structural gag proteins p24, p17, p7 and p6.
To date, most inhibitors of the HIV aspartic acid protease have been transition state mimetics. These have included reduced amides (Moore et al., Biochem. Biophys. Res. Commun. 159:420-425 (1989); Dreyer et al., Proc. Natl. Acad. Sci. 86:9752-9756 (1989)), hydroxyethylene isosteres (Dreyer et al., Proc. Natl. Acad. Sci. 86:9752-9756 (1989); Vacca et al., J. Med. Chem. 34:1225-1228 (1991); Tomasselli et al., J. Biol. Chem. 265: 14675-14683 (1990); Roberts et al., Science 248:358-361 (1990)), statine analogs (Dreyer et al., 1989), phosphinic acid derivatives (Grobelny et al., Biochem. Biophys. Res. Commun. 169:1111-1116 (1990)) and difluoroketone derivatives (Dreyer et al., 1989; Sham et al., Biochem. Biophys. Res. Commun. 175: 914-916 (1991)) .
HIV reverse transcriptase (RT) inhibitors can be grouped into two classes of compounds, nucleoside analogs and non-nucleoside RT inhibitors. Inhibition by either type of compounds results in the inhibition of virus replication in infected cells. Several nucleoside analogs, AZT, ddI, ddC, d4T and 3TC are currently in clinical trials or are approved for the treatment of HIV disease. These compounds act as competitive substrate inhibitors for the HIV RT following phosphorylation by cellular enzymes. Currently, no non-nucleoside RT inhibitors are approved but several, including TIBO (Pauwels et al., Nature 343:470-474 (1990)), nevirapine (Merluzzi et al., Science 250:1411-1413 (1990)), and L-697,661 (Goldman et al., Proc. Nat. Acad. Sci. (USA) 88: 6863-6867 (1991)) are being clinically evaluated. These compounds are non-competitive allosteric inhibitors or HIV RT.